Two independent reports issued Monday found Medtronic's spine surgery product known as Infuse offered little benefit over conventional spine surgery and may be linked to serious harms including cancer and a complication that can cause sterility in men.

The twist: This time the critical reviews were funded by Medtronic itself.

The studies amount to another rebuke of the biological agent, which stimulates bone growth and has been implanted in the spines of more than 1 million people, most who got it in unapproved ways, or so-called off-label use. As much as 80% of BMP-2 use is off-label.

"Spine surgeons are really going to have to be careful with using (Infuse)," said Dan Spengler, a professor of orthopedic surgery at Vanderbilt University Medical Center.

Spengler, who was not a part of the studies, predicted Medtronic and surgeons who have used the product could face lawsuits.

"There is going to be a liability storm," he said.

Infuse, known scientifically as bone morphogenetic protein-2, or BMP-2, once produced sales of nearly $1 billion a year, revenue that has fallen to $528 million after negative accounts about its safety and effectiveness.

At the heart of the controversy has been a small group of spine surgeons — including one at the University of Wisconsin-Madison — who got $210 million in royalties from Medtronic over the years while co-authoring papers that overstated the benefits of Infuse and downplayed its risks, even though the data was available.

None of the royalties were for Infuse.

Those surgeons, including UW's Thomas Zdeblick, factored into the new reports that were published online Monday in the journal Annals of Internal Medicine.

One report cited two papers Zdeblick co-authored that underreported adverse events linked to the product. Both papers were published in the Journal of Spinal Disorders & Techniques, where Zdeblick was editor-in-chief — a post he continues to hold.

One report issued Monday was from researchers at Oregon Health & Science University, the other from researchers at the University of York in the United Kingdom. Both were selected by the Yale researchers to do the studies.

The studies were paid for by Medtronic and used patient data supplied by the company. That virtually eliminates concerns — aired after earlier criticisms — that the findings were stacked against the company or the group of surgeons.

Theresearchers from Oregon Health & Science University said they found substantial evidence of biased reporting on BMP-2 in medical journals and no evidence that it is more effective than the traditional method used in spine surgery.

And they found evidence of a link to important harms, including a complication that can cause sterility in men; cancer; the formation of excess bone as well as wound healing problems, difficulty swallowing and speaking when it was used in the neck.

"It is hard to find a clear advantage for using it," said Mark Helfand, co-author of the report from Oregon Health & Science University, where he is a professor of medicine. "When you add in the potential harms, it tips the scale further toward not using it."

Charles Rosen, a spine surgeon who practices at the University of California-Irvine Medical Center, said the bony overgrowth can be pronounced and painful in patients who get Infuse in an unapproved manner.

In the last three months, he said, he has operated on five people to remove excess bone that was wrapped around nerve roots after they got Infuse.

"It is like cement around the nerves," said Rosen, who was not a part of the new studies.

In the other report, researchers from the University of York said that while BMP-2 improved pain and quality of life six to 24 months after surgery, those measures fell below "clinically meaningful thresholds."

And BMP-2 may double the risk of cancer, which occurred in 3% of those who got the substance within two years after surgery, the researchers found.

But the cancer risk was not definitive and had a wide range — from as low as 14% lower to 454% higher. Whether the risk is genuine is unknown, they wrote, but it is consistent with other research suggesting a link.

The fallout

Christine Laine, editor in chief of the Annals of Internal Medicine, said it now will be difficult for doctors to recommend BMP-2 since it was shown to offer no meaningful benefit over the traditional method used for spinal fusion.

Others were more harsh in their criticism.

U.S. Sen. Max Baucus (D-Mont.), chairman of the Senate Committee on Finance, said the new reports amounted to more evidence of "collusive relationships" between Medtronic and the doctors who wrote the questionable papers about Infuse.

Citing stories in the Journal Sentinel, in 2012 the finance committee did extensive investigation of those relationships, finding that Medtronic executives secretly were involved in drafting those stories.

"If not for those relationships and the misleading studies they produced, patients might have gotten more effective treatments and avoided harmful side effects," Baucus said in a statement. "The bottom line is ailing patients should never have to fear they're being sold a bill of goods. "

Eugene Carragee, editor in chief of the Spine Journal, which published its own critical review of BMP-2 in 2011, said early on there was an unwarranted carnival-like enthusiasm for the product.

The result, he said, was billions of dollars in extra medical costs and the increased risk of serious complications.

"The take-home message from this debacle...is that the public needs better safeguards against conflicted and tainted medical research," he said.

That means medical journals should have complete access to data and get unbiased presentations from authors, said Carragee, head of spine surgery at Stanford University.

"Unless we remain vigilant, medical publications will continue to devolve into information-laundering machines and clinical studies become infomercials for their corporate sponsors," he said.

Carragee noted that only a few months after Infuse was approved in 2002, UW's Zdeblick and other doctors who would get millions in royalties from Medtronic were touting the product.

In unusually glowing language, a 2003 paper they wrote declared the product could become "the new gold standard" in spine surgery and added that it was being used "exclusively" at their institutions.

The paper was published in the journal overseen by Zdeblick. The paper mentioned another Medtronic product, the LT-Cage, which is used with BMP-2 and for which Zdeblick receives royalties.

Last year, the Journal Sentinel reported Zedblick got more than $34 million, mostly in royalties, from Medtronic over a 15-year period. None of the royalties — or those of the other authors — of the 2003 paper were for BMP-2.

In an email to the Journal Sentinel, Zdeblick called Carragee "a crusader" and said his comments were "self-serving to say the least."

BMP-2 eliminates the need to harvest a small amount of bone from the pelvis of patients. Zdeblick said there is no evidence of higher complication rates when BMP-2 is used as approved and that because of that most patients would choose to have it for approved surgery.

"For (approved) surgery I exclusively use BMP with no evidence of increased complications," Zdeblick said.

He said he does not use BMP-2 for unapproved, or off-label, spine surgeries.

In a statement, Medtronic said it has worked with the U.S. Food and Drug Administration to communicate the risks and benefits of BMP-2 and that it reported complete adverse event information from clinical trials of the product to the FDA and on the product's label.

For the independent reviews it commissioned, Medtronic CEO Omar Ishrak said in a statement the company provided an unprecedented level of data access as a new way to test data-sharing of research.

"We recognize that our products and therapies must have the public and medical community's trust, so we will continue to create, test and explore new ways to make our clinical research available as part of a commitment to transparency," he said.

After Ishrak took over as CEO in 2011, Medtronic agreed to pay $2.5 million to fund the reviews that were issued Monday. The company agreed to have no control over the process.

"They deserve credit," said Harlan Krumholz, the Yale University professor of medicine who oversaw the project.

This story was reported as a joint project of the Journal Sentinel and MedPage Today. MedPage Today provides a clinical perspective for physicians on breaking medical news at medpagetoday.com.

About John Fauber

John Fauber is an investigative medical reporter who focuses on conflicts of interest in medicine and how drug and medical device companies and the FDA influence the practice of medicine. He has won more than two dozen national journalism awards.